Water → 4-(4-{5-amino-6-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester

HRID 1627575Notes

Reaction equation

HRID 1627575 reaction equation
[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]([NH2:24])=[N:15][CH:16]=[C:17]([C:19]2[CH:20]=[N:21][NH:22][CH:23]=2)[N:18]=1)[CH3:11].[H-].[Na+].[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37](OS(C)(=O)=O)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].O>CN(C=O)C>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([N:22]2[CH:23]=[C:19]([C:17]3[CH:16]=[N:15][C:14]([NH2:24])=[C:13]([O:12][C@@H:10]([C:3]4[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=4[Cl:1])[CH3:11])[N:18]=3)[CH:20]=[N:21]2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]

Participants

6

Reactant 4

HCID 962WaterHCID 24758Sodium hydrideHCID 41848691-(tert-Butoxycarbonyl)-4-(methanesulfonyloxy)piperidineHCID 115161713-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-(1H-pyrazol-4-yl)-pyrazin-2-ylamine

Product 1

HCID 596276034-(4-{5-amino-6-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl esterYield 60.1%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-(1H-pyrazol-4-yl)-pyrazin-2-ylamine (295 mg, 0.80 mmol) in anhydrous DMF (4 mL) was added NaH (60% in mineral oil, 30.7 mg, 0.80 mmol). The mixture was stirred at ambient temperature under nitrogen for 0.5 h, and then 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (223.5 mg, 0.80 mmol) was introduced. The reaction mixture was heated to 90° C. oil bath for 0.5 h under nitrogen, and cooled to ambient temperature. Water was added slowly to the mixture, which was extracted with EtOAc, washed with brine, and dried over Na2SO4. The crude product was purified on a silica gel column to provide 4-(4-{5-amino-6-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (265 mg, 59% yield).

Workup

  1. temperatureThe reaction mixture was heated to 90° C. oil bath for 0.5 h under nitrogen
  2. temperaturecooled to ambient temperature
  3. extractionwas extracted with EtOAc
  4. washwashed with brine
  5. dry with materialdried over Na2SO4
  6. customThe crude product was purified on a silica gel column

Sources & evidence

ORD record
ord-261667f18e6d4c92b1e4ec7c2443f400
Source dataset
uspto-grants-2014_07
Patent number
US08785632B2

Reaction notes

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